tbuckley/cabot-search huggingface dataset:
S227: SBNO2 IS A SPECIFIC DEPENDENCY OF STAT3-DRIVEN T-CELL MALIGNANCIES
Authors: T. Brandstoetter, B. Maurer, J. Schmoellerl, S. Kollmann, J. Huuhtanen, R. Grausenburger, S. Mustjoki, J. Zuber, V. Sexl
Journal: HemaSphere (2022)

Background: The transcription factor signal transducer and activator of transcription 3 (STAT3) plays important roles in regulating the survival, growth and differentiation of hematopoietic cells, particularly within the lymphoid lineage. Recently, gain-of-function mutations within the SH2 domain of STAT3 have been identified in patients suffering from T-cell large granular lymphocytic leukemia (T-LGLL). The most frequently found hyperactivating mutation represents STAT3Y640F. Aims: Transcription factors are notoriously difficult to target, hence a better understanding of STAT3-dependent transcriptional co-factors and their molecular targets is critical to identify novel therapeutic approaches. Methods: To unravel the molecular mechanisms behind STAT3Y640F-induced malignancies, we developed a murine in vitro model that recapitulates common transcriptional features that are found in CD8+ transformed T-LGLL cells from patients harbouring STAT3 mutations. Gene expression analyses and chromatin occupancy profiling of mutated STAT3Y640F identified a core set of direct transcriptional targets, which were interrogated for their functional relevance in genome-wide CRISPR/Cas9-based loss-of-function screens. Results: Expression of STAT3Y640F blocked differentiation of murine hematopoietic stem and progenitor cells (mHSPC), enhanced their self-renewal capacity and increased proliferation in comparison to wild type STAT3 expressing cells. Mechanistically, the STAT3Y640F mutation led to increased and prolonged activation of STAT3 signalling and decreased their dependence on cytokine stimulation. In contrast to mHSPC expressing wild-type STAT3, the Y640F-mutated variant resulted in a strong inflammatory gene expression signature that was characterized by overactivation of TNF alpha/Interferon gamma pathways, and is conserved in T-LGLL patients harbouring STAT3 mutations. Through genome-wide loss-of-function screens using CRISPR/Cas9 we identified that the transcriptional co-regulator strawberry notch homolog 2 (SBNO2) is an essential direct transcriptional target of STAT3Y640F in transformed mHSPC. SBNO2 was overexpressed in both, STAT3Y640F-transformed mHSPC (versus STAT3WT) and T-LGLL patients harbouring STAT3 mutations (versus T-LGLL patients with wild type STAT3). As seen with loss of STAT3-Y640F expression, loss of SBNO2 also impaired proliferation of transformed mHSPC. Strikingly, global analyses of gene dependency datasets revealed that various human T-cell malignancies that are driven by aberrant STAT3 signalling depend on SBNO2 expression. Summary/Conclusion: Together, our data show that the STAT3/SBNO2 axis could be a promising therapeutic intervention site in STAT3 driven T-cell malignancies.
Reporting of Statistical Inference in Abstracts of Major Cancer Journals, 1990 to 2020
Authors: Andreas Stang, Börge Schmidt
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Since the 1990s, reporting guidelines have developed that uniformly require authors to report a measure of precision (confidence intervals [CIs]) in addition to effect size. <h3>Objective</h3> To investigate the time trend of statistical inference and statistical reporting style in abstracts of major cancer journals. <h3>Design, Setting, and Participants</h3> This cross-sectional study reviewed all abstracts published between January 1, 1990, and December 31, 2020, in 10 high-ranking cancer journals (<i>Lancet Oncology</i>,<i>Journal of Clinical Oncology</i>,<i>Cancer Discovery</i>,<i>Cancer Cell</i>,<i>JAMA Oncology</i>,<i>Annals of Oncology</i>,<i>Molecular Cancer</i>,<i>Journal of Thoracic Oncology</i>,<i>Journal of the National Cancer Institute</i>, and<i>Trends in Cancer</i>) using a previously validated computerized algorithm to search the PubMed database. For the time trend analyses, 2 journals with only a few years of existence (<i>JAMA Oncology</i>and<i>Trends in Cancer</i>) were excluded. <h3>Exposures</h3> Calendar year, journal, and type of abstract (randomized clinical trial or other). <h3>Main Outcomes and Measures</h3> Proportions of abstracts containing CIs,<i>P</i>values without CIs, and qualitative expressions of statistical significance only were compared over time among journals. <h3>Results</h3> Overall, 24 034 of 42 509 abstracts (56.5%) contained statistical inference. Reporting of CIs increased over time in 5 of 8 journals. From 2016 to 2020, the most prevailing statistical reporting style was the presentation of CIs (3070 of 4895 [62.7%]). However, the proportion of abstracts reporting statistical inference based solely on the terms<i>significant</i>or<i>nonsignificant</i>was still 1195 of 4895 (24.4%) during this period and was most prevalent among basic science–oriented cancer journals (eg, 63 of 66 [95.5%] in<i>Cancer Cell</i>). A higher prevalence of CI reporting was associated with reporting of results from randomized clinical trials and the requirement to report according to guidelines (eg, 522 of 574 [90.9%] in<i>Lancet Oncology</i>). <h3>Conclusions and Relevance</h3> These findings suggest that the reporting style of statistical inference in abstracts of major cancer journals has improved over time. A requirement in journals’ instructions for authors to present statistical inference in accordance with reporting guidelines and the implementation of these guidelines in submitted manuscripts on the part of journal editors may improve reporting.
P484: WHOLE EXOME SEQUENCING (WES) CHARACTERIZES THE MUTATIONAL LANDSCAPE OF BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM (BPDCN)
Authors: H. Witte, A. Kuenstner, J. Schwarting, V. Bernard, H. Merz, N. von Bubnoff, H. Busch, A. Feller, N. Gebauer
Journal: HemaSphere (2022)

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and clinically aggressive hematologic malignancy. Due to novel technologies pathogenetic concepts of BPDCN underlie a dynamic process. However, its genomic features including novel therapeutic vulnerabilities remain sparsely characterized. Aims: The present study aimed to illustrate the mutational landscape of BPDCN. Methods: To delineate the mutational landscape of BPDCN, whole-exome sequencing (WES) of 47 cases was performed. Significantly mutated genes, oncogenic drivers and perturbed pathways were compared with data from acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). Results: Median age was 73 years (range 26 – 91) and 72.3% were male. Primary involvement of the skin and the bone marrow was present in 28 (59.6%) and 15 (34.9%) cases, respectively. A median of 98 mutations per sample was detected resulting in a tumor mutational burden (TMB) of 2.57 mutations/Mb/sample. WES and consecutive gene set enrichment analysis revealed an accumulation of oncogenic mutations in epigenetic regulators of gene-expression (95.7% of cases; TET2, DNMT3A, KMT2D, SETD2, IDH2), RTK-RAS (93.6%; NRAS, MET, EGFR), NOTCH (76.6%; NOTCH2, CREBBP, EP300) and WNT signaling pathways (59.6%; CTNNB1, MED12). Moreover, WES identified a subset of shared myeloid drivers across the spectrum of BPDCN, AML and CMML. In the era of precision oncology, exome profiling revealed several potential therapeutic targets such as NOTCH2, NRAS, EGFR or EZH2. Summary/Conclusion: To the best of our knowledge, we provide genomic profiling in the largest WES cohort in BPDCN to date. Current results confirmed previous genomic features associated with myeloid pathogenesis, identified additional significantly mutated drivers and novel potential therapeutic vulnerabilities.
Maternal Vaccination and Risk of Hospitalization for Covid-19 among Infants
Authors: Natasha B. Halasa, Samantha M. Olson, Mary A. Staat, Margaret M. Newhams, Ashley M. Price, Pia S. Pannaraj, Julie A. Boom, Leila C. Sahni, Kathleen Chiotos, Melissa A. Cameron, Katherine E. Bline, Charlotte V. Hobbs, Aline B. Maddux, Bria M. Coates, Kelly N. Michelson, Sabrina M. Heidemann, Katherine Irby, Ryan A. Nofziger, Elizabeth H. Mack, Laura Smallcomb, Stephanie P. Schwartz, Tracie C. Walker, Shira J. Gertz, Jennifer E. Schuster, Satoshi Kamidani, Keiko M. Tarquinio, Samina S. Bhumbra, Mia Maamari, Janet R. Hume, Hillary Crandall, Emily R. Levy, Matt S. Zinter, Tamara T. Bradford, Heidi R. Flori, Melissa L. Cullimore, Michele Kong, Natalie Z. Cvijanovich, Suzanne M. Gilboa, Kara N. Polen, Angela P. Campbell, Adrienne G. Randolph, Manish M. Patel
Journal: New England Journal of Medicine (2022)

Infants younger than 6 months of age are at high risk for complications of coronavirus disease 2019 (Covid-19) and are not eligible for vaccination. Transplacental transfer of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after maternal Covid-19 vaccination may confer protection against Covid-19 in infants.
P1196: DIFFERENT MUTATIONS IN PATIENTS WITH PRIMARY LARGE B-CELL LYMPHOMA
Authors: I. Kamaeva, I. Lysenko, N. Nikolaeva, O. Kit, I. Novikova, Y. Gaysultanova
Journal: HemaSphere (2022)

Background: Primary mediastinal large B-cell lymphoma (PMBCL) is a type of aggressive large B-cell lymphoma which affects mainly young patients and is characterized by a local spread and development of a tumor conglomerate in the mediastinum. One of the most important pathogenetic mechanisms of the development of PMBCLs is their genetic heterogenety. There are a lot of similarities between molecular profiles of diffuse large B-cell lymphoma, Hodgkin’s lymphoma, and gray zone lymphoma, which are described in the literature. However, there is no clear molecular-genetic characteristic of PMBCL. Despite the successful treatment of patients with modern methods of immunochemotherapy, a large number of patients are resistant to the therapy due to the tumor heterogeneity. The aim of this study was the detection of a clinically significant mutation for patients with PMBCL by next-generation sequencing. Aims: To identify significant mutations in the genes in patients with PMBCL for the further studies. Methods: The study included 47 patients diagnosed with different stages of PMBCL who received treatment from 2013 to 2021. NGS was performed using the AVENIO Tumor Expanded Panel, Roche, USA, which includes 77 genes. DNA was isolated using the Gene Read DNA FFPE Kit panel, Qiagen, USA. The data were processed using the AVENIO Oncology Analysis Software to search for clinically significant mutations. The mutations were also confirmed by Sanger sequencing. Results: The genetic material of selected patients was analyzed for the presence of clinically significant mutations among the known databases: COSMIC: v83, TCGA 9.0, ExAC:1.0, dbSNP:150, 1000 Genomes: phase_3_v5b, SnpEff:4.2. A missense variant of clinically significant mutations in the FGFR3, PIK3CA, ALK, EZH2, RNF43, MET genes was identified in patients with refractory PMBCL. For example, an activating driver mutation in the FGFR3 gene was detected in the 9th exon (rs121913479), which is pathogenic. The frequency of alleles was 25.54%. An activating driver mutation in the PIK3CA gene was detected in the 10th exon (rs121913273), which is also pathogenic. The frequency of alleles was 10.88%. The aim of the study was to identify signaling pathways which were related to mutated genes. They were PI3K-AKT, JAK-STAT, RAP1, RAS, MAPK, stem cell regulation signaling pathway, which were also interpreted. According to the bioinformatics analysis, FGF/FGFR3 was the most significant signaling pathway for PMBCL in our study, because it is able to activate all listed pathways via FGFR-receptor activation. Summary/Conclusion: NGS revealed clinically significant mutations in the genes in patients with PMBCL, the therapeutic potential of which requires the further studies.
Associations Between Handgrip Strength and Dementia Risk, Cognition, and Neuroimaging Outcomes in the UK Biobank Cohort Study
Authors: Kate A. Duchowny, Sarah F. Ackley, Willa D. Brenowitz, Jingxuan Wang, Scott C. Zimmerman, Michelle R. Caunca, M. Maria Glymour
Journal: JAMA Network Open (2022)

<h3>Importance</h3> The associations between muscle strength and cognitive outcomes have sparked interest in interventions that increase muscle strength for prevention of dementia, but the associations between muscle strength and cognitive aging are unclear, particularly among middle-aged adults. <h3>Objective</h3> To evaluate the association between handgrip strength (HGS) and dementia, reduced cognition, and poorer neuroimaging outcomes in a UK population of middle-aged adults. <h3>Design, Setting, and Participants</h3> This cohort study evaluated UK Biobank participants aged 39 to 73 years enrolled from 2006 to 2010 with measured HGS and prospectively followed up for dementia diagnosis. Data were analyzed from October 2021 to April 2022. <h3>Exposures</h3> HGS assessed in both hands via dynamometer. <h3>Main Outcomes and Measures</h3> Outcomes included cognitive test scores (fluid intelligence and prospective memory), brain magnetic resonance imaging measures (total brain volume, white matter hyperintensity, and hippocampal volume), and incident dementia (all-cause, vascular, and Alzheimer disease [AD] from primary care, hospital, or death records) over a median (IQR) of 11.7 (11.0-12.4) years of follow-up. Mixed-effects linear and logistic regressions and Cox proportional-hazard models were used to estimate associations, stratified by gender and adjusted for covariates. Estimates are presented per 5-kg decrement in HGS. To evaluate reverse causation, we assessed whether a polygenic risk score for AD is associated with HGS. <h3>Results</h3> A subsample of 190 406 adult participants in the UK Biobank (mean [SD] age, 56.5 [8.1] years; 102 735 women [54%]) were evaluated. A 5-kg decrement in HGS was associated with lower fluid intelligence scores in men (β, –0.007; 95% CI, –0.010 to –0.003) and women (β, –0.04; 95% CI, –0.05 to –0.04. A 5-kg decrement in HGS was associated with worse odds of correctly responding to a prospective memory task for men (odds ratio, 0.91; 95% CI, 0.90 to 0.92) and women (odds ratio, 0.88; 95% CI, 0.87 to 0.90). A 5-kg decrement in HGS was associated with greater white matter hyperintensity volume in men (β, 92.22; 95% CI, 31.09 to 153.35) and women (β, 83.56; 95% CI, 13.54 to 153.58). A 5-kg decrement in HGS was associated with incident dementia for men (hazard ratio, 1.20; 95% CI, 1.12 to 1.28) and women (hazard ratio, 1.12; 95% CI, 1.00 to 1.26). The AD genetic risk score was not significantly associated with HGS. <h3>Conclusions and Relevance</h3> These findings suggest that HGS is associated with measures of neurocognitive brain health among men and women and they add to a growing body of research indicating that interventions designed to increase muscle strength, particularly among middle-aged adults, may hold promise for the maintenance of neurocognitive brain health.
P333: MULTI-COHORT GENE EXPRESSION RESOURCE FOR AUTOMATIC SUBTYPING OF B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: V.-P. Mäkinen, J. Rehn, J. Breen, D. Yeung, D. White
Journal: HemaSphere (2022)

Background: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and comprises multiple distinguishable genomic subtypes. RNA sequencing provides a functional snapshot that we propose will provide rapid diagnostic information for most ALL subtypes and deep biological insight to guide diagnostic efforts of atypical cases. Aims: The aims of this study were to elucidate the predictive associations between mRNA-seq profiles and independently verified genomic lesions, and to develop easy-to-interpret transcriptome-wide biomarkers for ALL subtyping in the clinical setting. Methods: A total of 1,279 ALL patients were included in the discovery dataset from six publicly available North American cohorts and 767 Australian ALL patients were included as an external validation cohort. Additional publicly available mRNA-seq data (n = 1,160) were used for quality control modelling. A novel batch correction method was introduced and applied to adjust for cohort differences. Three machine learning models (random forest, projections to latent structures and nearest Euclidean neighbor) were trained with the discovery set and validated in the Australian dataset. Results: Out of 18,503 genes with usable expression, 11,830 (64%) were confounded by cohort effects and excluded. There were no substantial differences between the machine learning methods in the validation set; we chose the nearest neighbor technique as the simplest alternative. Six ALL subtypes (ETV6-RUNX1, KMT2A, DUX4, PAX5 P80R, TCF3-PBX1, ZNF384) that covered 32% of patients were robustly detected by mRNA-seq (PPV ≥ 87%). Five other frequent subtypes (CRLF2, hypodiploid, hyperdiploid, PAX5 alterations and Ph-positive) were distinguishable in 40% of patients, although overlapping transcriptional profiles led to lower accuracy (52% ≤ PPV ≤ 73%). Based on these findings, we developed the Allspice R package that predicts ALL subtypes and driver genes from unadjusted mRNA-seq read counts as encountered in real-world settings. Image:Summary/Conclusion: We demonstrated high diagnostic accuracy for a fully automated mRNA-seq method for a third of ALL patients and additional contribution to diagnostic efforts for patients with inconclusive or mixed genomic characteristics.
P779: OPTIMIZING TREATMENT OUTCOMES FOR CHILDREN WITH HIGHER-RISK MYELODYSPLASTIC SYNDROME UNDERGOING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
Authors: Y. Ren, F. Liu, X. Chen, X. Li, L. Liu, W. Yang, Y. Guo, X. Zhu
Journal: HemaSphere (2022)

Background: Myelodysplastic syndrome (MDS) are rare clonal hematopoietic disorders in children. Risk stratification system for adults is unfit for children. Refractory anemia with excess blasts(RAEB), acute myeloid leukemia with myelodysplasia-related changes(AML-MRC), monosomy 7 and complex karyotype always indicate poor prognosis. Hypomethylating agent (HMA) improved survivals of high-risk MDS in adults, and decitabine as part of conditioning regimen for allogenetic hematopoietic stem cell transplantation(allo-HSCT) was associated with favorable outcomes. However, these findings have not been tested in pediatric cohorts broadly. Aims: To evalute the efficacy and safety of hypomethylating agents as a part of pre-transplant treatments and contidioning regimens in children with higher-risk MDS. Methods: Patients from 1 to 14 years of age who were diagnosed with higher-risk MDS and underwent allo-HSCT consecutively between February 2019 and August 2020 in Pediatric Blood Diseases Center were enrolled. All identified patients were retrospectively reviewed with a collection of clinical data, laboratory test results, and outcome. Results: We reviewed 18 pediatric patients with higher-risk MDS, including 7 with RAEB, 8 with AML-MRC, and 3 with refractory cytopenia of childhood with monosomy 7. Regardless of initial diagnosis, monosomy 7 is the most common cytogenetic aberration (8/18, 44.4%). Next-generation sequencing (NGS) was performed on 15 specimens and the most frequent detection of mutation gene was SETBP1, followed by ETV6. Before transplantation, ten patients received monotherapies or combined chemotherapies with HMA, two patients received AML-like chemotherapies, and nine of those achieved bone marrow complete remission. The stem cell sources came from matched sibling donor (n=1), haploidentical donor (n=11), and unrelated cord blood (n=6), respectively. Low-dose decitabine-containing myeloablative conditioning regimens were administered in all cases. About 50% of patients (n=9) experienced Grade II- IV acute graft versus host diseases post-transplant. The cumulative incidence of transplantation-related mortality (TRM) was 11.1%. During a median follow-up of 10.5 (range, 2–36) months after transplantation, 15 of 18 patients were alive. At time of last follow-up, all survivors had resolution of hematologic disorder without relapse. Summary/Conclusion: In summary, administration of hypomethylating agents to allogeneic SCT resulted in excellent outcomes in children with higher-risk MDS.
P1442: DYNAMIC LANDSCAPE OF PLASMA PROTEOME AND METABOLOME IN B-ALL PATIENTS DURING CAR-T CELL THERAPY
Authors: J. Wu, L. Tang, M. Du, C. Li, H. Kou, H. Jiang, W. Luo, Y. Zhang, Z. Huang, W. Xiong, H. Mei, Y. Hu
Journal: HemaSphere (2022)

Background: Poor understanding of plasma proteomic and metabolomic features during chimeric antigen receptor (CAR) T cell therapy may affect the exploitation of therapeutic potential in the management of hematological malignancies. Aims: This word was designed to illustrate the dynamic landscape of plasma proteome and metabolome in B-ALL patients during CAR-T cell therapy and detailed the kinetics of proteins and metabolites during cytokines storm. Methods: In this study, we performed proteomic and metabolomic profiling of plasma from 20 patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) on CAR-T cell therapy and 22 healthy controls. Results: We identified molecular changes in the plasma of B-ALL patients compared to healthy controls. Many of the changes involved actin cytoskeleton organization, acute-phase responses, autophagy, branched-chain amino acid, and lipid metabolism (Figure A). Furthermore, CAR-T cell therapy reshaped plasma proteome and metabolome with discrete kinetics, as represented by upregulated acute-phase response and triglycerides metabolism and downregulated actin cytoskeleton organization, axon extension, retrograde endocannabinoid signaling, autophagy, and glycosylphosphatidylinositol (GPI)-anchor biosynthesis during the therapy (Figure B). Moreover, we identified sets of covarying molecules involved in the acute inflammatory response, epithelial-mesenchymal transition, glutathione metabolism, and tryptophan metabolism and change in concert with the dynamics of circulating IL-6 in patients with cytokines storm (Figure C). Subgroup analysis further revealed numerous prognostic biomarkers, such as proteins related to allograft rejection, which were down-regulated in patients who achieved stable complete remission. Image:Summary/Conclusion: This study provided a dynamic landscape of plasma proteome and metabolome in B-ALL patients during CAR-T cell therapy and offered novel insights into the pathogenesis of B-ALL and CAR-T cell therapy-related toxicities.
Prophylactic Antibiotic Regimens in Tumor Resection Surgery Involving a Prosthesis
Authors: Karin Veerman, Heiman Wertheim
Journal: JAMA Oncology (2022)

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